DNA mismatch repair (MMR) maintains genetic stability by correcting mismatches, initiating apoptosis in response to several forms of irreparable DNA damage, and suppressing homologous recombination. Mutational or epigenetic inactivation of MMR causes profound genetic instability and underlies several inherited and sporadic forms of cancer. The therapeutic importance of MMR is highlighted by the fact that tumor cells lacking MMR resist to the cytotoxic effects of several common anticancer drugs. Previous research has been focused on understanding MMR in the context of naked DNA, and little is known about the action of MMR in the nucleosomal environment. Our preliminary data support the overarching hypothesis that there is active interplay and cooperation between the actions of MMR and the nucleosomal environment. The goal of the proposed research is to comprehensively test this hypothesis. Our first aim is to investigate the apoptotic function of MMR in the context of the nucleosomal environment. Our second aim is to study the impact of the nucleosomal environment on the mismatch correction function of MMR. Our third aim is to examine the cooperation between the mismatch correction function of MMR and histone H3-K56 acetylation in promoting genetic stability. To achieve these aims we will take advantage of our unique expertise in performing genetic, biochemical, and molecular biology studies of MMR. The obtained results will significantly contribute to our understanding of the action of human MMR and the potential of using histone chaperone inhibitors for improving the effects of the anticancer drugs.